Advanced Breast Cancer

SAN ANTONIO—For postmenopausal women with advanced breast cancer with disease progression on non-steroidal aromatase inhibitor therapy, treatment with the selective estrogen-receptor (ER) downregulator fulvestrant is a safe and effective option, researchers reported at the San Antonio Breast Cancer Symposium. In the randomized study, various clinical endpoints, including time to disease progression, response rate, and clinical benefit rate, were virtually identical” among women given the oral steroidal aromatase inhibitor exemestane and those given injectable fulvestrant, reported William J. Gradishar, MD, Director of Breast Medical Oncology and Professor of Medicine at the Robert H. Lurie Comprehensive Cancer Center at Northwestern University Feinberg School of Medicine. “Equally importantly, the tolerability of both drugs was equivalent,” he said. While fulvestrant has been used in this setting for some time, there has been some concern that the selective ER downregulator might not be as tolerable or effective as a steroidal aromatase inhibitor, he said. Dr. Gradishar's report was the first Phase III trial to examine endocrine sequencing in women whose breast cancer progressed or recurred while on adjuvant treatment with non-steroidal aromatase inhibitors. Also at the meeting, researchers explored the side effects, chiefly joint complaints, associated with endocrine therapy as well as newer, more potent bisphosphonates to combat aromatase inhibitor-associated bone loss. EFECT Trial The new study, known as the Evaluation of Fulvestrant versus Exemestane Clinical Trial (EFECT), enrolled 693 women whose cancer had progressed or who had suffered a recurrence while they were being treated with a nonsteroidal aromatase inhibitor or within six months of its discontinuation. To be eligible, women had to have measurable disease or bone lesions, normal organ function, and a performance status of two or lower. Women were disqualified if they had life-threatening visceral metastases or brain or leptomeningeal involvement. The median age of participants, about 90% of whom were Caucasian, was 63. About two-thirds had bone metastases, one-third had metastases to the lung, and one-third had liver metastases. Just over half, 53%, of the women in the trial had taken two or more previous hormonal therapies. Dr. Gradishar said that the study had a double-blind, double-dummy design, with patients assigned to either 25 mg/day of oral exemestane plus an injected placebo, or injected fulvestrant plus oral placebo. Fulvestrant was front-loaded in order to achieve a steady plasma state as quickly as possible, with 500 mg on Day 1, followed by 250 mg on Days 14 and 28, and 250 mg every 28 days afterward.Figure: The trial reported by William J. Gradishar, MD, was the first Phase III trial to examine endocrine sequencing in women whose breast cancer progressed or recurred while on adjuvant treatment with non-steroidal aromatase inhibitors. Clinical endpoints, including time to disease progression, response rate, and clinical benefit rate, were virtually identical among women given the oral steroidal aromatase inhibitor exemestane and those given injectable fulvestrant.Drugs Perform Equally Well Results showed that for the primary endpoint, time to progression, there was no difference between the two study arms: 3.7 months in both groups. There was also no meaningful difference in the objective response rate—7.4% for fulvestrant vs 6.7% for exemestane. The clinical benefit rate, defined as an objective response plus stable disease for 24 or more weeks, was also similar among the two arms: 32.2% for fulvestrant vs 31.5% for exemestane. Among patients who responded, the duration of response was 13.5 months for fulvestrant and 9.8 months for exemestane—again a nonsignificant difference. As for tolerability, 88.9% of patients on fulvestrant and 88.8% of patients on exemestane had an adverse effect. Grade 3 or higher adverse effects developed in 21.7% of patients on fulvestrant and 22.6% of patients on exemestane. “There was also no difference in the rate of drug-related adverse effects, withdrawals due to adverse effects, serious adverse events, or drug-related serious adverse effects. In all measures of adverse events, in fact, the two drugs were comparable,” Dr. Gradishar said. “The overall modeling that suggested that the loading dose of fulvestrant would be important to achieving good results was confirmed in pharmacokinetic studies performed as part of the trial.” Two Good Options “The bottom line,” Dr. Gradishar said, “is that these data assure clinicians that whichever endocrine therapy they choose in this setting, they will not be compromising the chance of patient benefit.” A co-moderator of the session at which the study was reported, George W. Sledge, Jr., MD, the Ballve-Lantero Professor in the Department of Medicine, Division of Hematology/Oncology, at Indiana University, said that based on these findings, he agreed. Given that both treatments appear to be safe and effective for patients with metastatic breast cancer, patient and physician preference may play a key role in choosing therapy, he said. Dr. Sledge said that in his practice, most patients prefer pills to shots. But there are cases, such as if compliance is a problem, when an intravenous agent may be a better option. One surprising finding was the comparable tolerability of the agents, he noted. Based on both clinical practice and the scientific literature, “I would have expected more arthritic complaints among patients receiving the steroidal aromatase inhibitor,” he said in an interview. AI Side Effects Two surveys presented at the meeting, while conducted in women with earlier-stage breast cancer, also point to an association between joint problems and the steroidal aromatase inhibitors exemestane, anastrozole, and letrozole (Femara).Figure: George W. Sledge, Jr., MD: “Given that both fulvestrant and exemestane appear to be safe and effective for patients with metastatic breast cancer, patient and physician preference may play a key role in choosing therapy.’’In an online survey conduced by the Breast Cancer Action advocacy group, nearly 30% of the 612 respondents said they discontinued therapy, 87% because of intolerable adverse events and 47% due to joint-related problems. Other side effects reported by more than half of the respondents included stroke, cough, arm or leg edema, flu-like symptoms, and anxiety. For the survey, the researchers asked whether women experienced any of 38 adverse events associated with the steroidal aromatase inhibitors that appear on the product labeling as well as any unlisted adverse events. A second survey of 200 postmenopausal women receiving adjuvant aromatase inhibitors for early-stage breast cancer found that 47% of women experienced drug-related joint pain and 44% had drug-related joint stiffness. Katherine D. Crew, MD, and colleagues at the Herbert Irving Comprehensive Cancer Center at Columbia University, noted in their poster presentation that in large adjuvant trials, up to 30% of women reported suffering from musculoskeletal disorders and nearly 5% of patients discontinued therapy due to adverse events. “Because the success of aromatase inhibitor therapy depends upon patients' ability to adhere to treatment recommendations, further studies of interventions that may alleviate these symptoms and increase patients quality of life are needed,” they concluded. Bisphosphonate Therapy Also at the meeting, researchers reported that the third-generation bisphosphonate zoledronic acid (Zometa) appears to prevent aromatase inhibitor-associated bone loss among early-stage breast cancer patients. Two-year interim results of the study, know as Z-FAST (Zometa-Femara Adjuvant Synergy Trial), showed that among women on letrozole, intravenous zoledronic acid improved spine and hip bone density. “Upfront zoledronic acid increased lumbar spine bone mineral density 5.9% and total hip bone mineral density by 4.7% compared with patients who were on a delayed start of bisphosphonate therapy,” reported Adam M. Brufsky, MD, PhD, Assistant Professor of Medicine at Magee-Womens Hospital of the University of Pittsburgh Medical Center. The study included 602 patients assigned to letrozole therapy. Half were randomly assigned to receive zoledronic acid from the outset. The other were given zoledronic acid only if there was a marked decrease in bone mineral density or if the patient suffered a fracture or bone complication after starting letrozole treatment. In another new study, Canadian researchers found that second-line therapy with oral ibandronate provided significant palliative benefit to metastatic breast cancer patients who had bony progression or a skeletal-related event on first-line bisphosphonate therapy. Lead author Mark J. Clemons, MD, Head of Breast Medical Oncology at Princess Margaret Hospital in Toronto, said that despite treatment with oral clodronate or intravenous pamidronate, a substantial number of metastatic breast cancer patients have bony progression or develop a skeletal-related event. In his study of 30 such patients, 12 weeks of second-line treatment with 50 mg/day of oral ibandronate resulted in a statistically significant improvement in pain control on the Brief Pain Inventory by Week 12. Of the 23 patients who initially received intravenous pamidronate, 20 (87.0%) said they preferred oral therapy. In clinical practice, most patients with bony progression or skeletal-related events are maintained on the same bisphosphonate without any supportive evidence,” Dr. Clemons said. “If these findings are confirmed through randomized trials, clinicians can start breaking away from this paradigm.”

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